EP3558951B1 - Method for the manufacturing of delmopinol - Google Patents
Method for the manufacturing of delmopinol Download PDFInfo
- Publication number
- EP3558951B1 EP3558951B1 EP17821624.8A EP17821624A EP3558951B1 EP 3558951 B1 EP3558951 B1 EP 3558951B1 EP 17821624 A EP17821624 A EP 17821624A EP 3558951 B1 EP3558951 B1 EP 3558951B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- propylhept
- delmopinol
- ene
- process according
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims description 114
- QSFOWAYMMZCQNF-UHFFFAOYSA-N delmopinol Chemical compound CCCC(CCC)CCCC1COCCN1CCO QSFOWAYMMZCQNF-UHFFFAOYSA-N 0.000 title claims description 88
- 229960003854 delmopinol Drugs 0.000 title claims description 79
- 238000004519 manufacturing process Methods 0.000 title claims description 19
- 230000008569 process Effects 0.000 claims description 95
- 239000002253 acid Substances 0.000 claims description 36
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 26
- -1 (4-propylhept-3-en-1-yl)magnesium halide Chemical class 0.000 claims description 21
- MAUROQBEYZVLDD-UHFFFAOYSA-N 2-[3-(4-propylhept-3-enyl)morpholin-4-yl]ethanol Chemical compound C(CC)C(=CCCC1COCCN1CCO)CCC MAUROQBEYZVLDD-UHFFFAOYSA-N 0.000 claims description 21
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 18
- 229960000649 oxyphenbutazone Drugs 0.000 claims description 17
- 239000007818 Grignard reagent Substances 0.000 claims description 12
- 150000004795 grignard reagents Chemical class 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical class N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 claims 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 57
- 239000000203 mixture Substances 0.000 description 41
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 26
- 239000000243 solution Substances 0.000 description 24
- 239000008194 pharmaceutical composition Substances 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 18
- RDPAULPKGBQFNT-UHFFFAOYSA-N 1-chloro-4-propylhept-3-ene Chemical compound ClCCC=C(CCC)CCC RDPAULPKGBQFNT-UHFFFAOYSA-N 0.000 description 17
- NPAQHMKTILVGKK-UHFFFAOYSA-N 4-cyclopropylheptan-4-ol Chemical compound CCCC(O)(CCC)C1CC1 NPAQHMKTILVGKK-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000004817 gas chromatography Methods 0.000 description 15
- JNECXFDDUQAPLC-UHFFFAOYSA-N 1-bromo-4-propylhept-3-ene Chemical compound BrCCC=C(CCC)CCC JNECXFDDUQAPLC-UHFFFAOYSA-N 0.000 description 14
- CNDQSXOVEQXJOE-UHFFFAOYSA-N oxyphenbutazone hydrate Chemical compound O.O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 CNDQSXOVEQXJOE-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 9
- 230000009466 transformation Effects 0.000 description 9
- FBLFIHQPSPSEIA-UHFFFAOYSA-N 4-propylheptan-1-ol Chemical compound CCCC(CCC)CCCO FBLFIHQPSPSEIA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- PKAHQJNJPDVTDP-UHFFFAOYSA-N methyl cyclopropanecarboxylate Chemical compound COC(=O)C1CC1 PKAHQJNJPDVTDP-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- SSHIAUSSHLAQRI-UHFFFAOYSA-N 1-iodo-4-propylhept-3-ene Chemical compound ICCC=C(CCC)CCC SSHIAUSSHLAQRI-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- 208000007565 gingivitis Diseases 0.000 description 6
- 230000007505 plaque formation Effects 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 229940034610 toothpaste Drugs 0.000 description 6
- 239000000606 toothpaste Substances 0.000 description 6
- 208000025157 Oral disease Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001030 gas--liquid chromatography Methods 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 description 5
- 208000030194 mouth disease Diseases 0.000 description 5
- 229940095518 mouthwash product Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 229950000188 halopropane Drugs 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- JYZUFTSYNSOVNI-UHFFFAOYSA-N 1-bromo-4-propylheptane Chemical compound CCCC(CCC)CCCBr JYZUFTSYNSOVNI-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 3
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000002346 iodo group Chemical group I* 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000003918 potentiometric titration Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000002734 organomagnesium group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- FIGMLQAGUUMXMJ-UHFFFAOYSA-N 1-cyclopropylheptan-4-ol Chemical compound CCCC(O)CCCC1CC1 FIGMLQAGUUMXMJ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JFZBMJJFVBMZNC-UHFFFAOYSA-N 2-[3-(4-propylheptyl)morpholin-4-yl]ethanol;hydrochloride Chemical compound Cl.CCCC(CCC)CCCC1COCCN1CCO JFZBMJJFVBMZNC-UHFFFAOYSA-N 0.000 description 1
- LASHFHLFDRTERB-UHFFFAOYSA-N 2-propylpentan-1-ol Chemical compound CCCC(CO)CCC LASHFHLFDRTERB-UHFFFAOYSA-N 0.000 description 1
- HCFAJYNVAYBARA-UHFFFAOYSA-N 4-heptanone Chemical compound CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 description 1
- JEVSSCXTVQHWCX-UHFFFAOYSA-N 4-propylhept-3-ene Chemical compound CCCC(CCC)=CCC JEVSSCXTVQHWCX-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- NNSDCLUPQZHWMT-UHFFFAOYSA-M C(CC)C(=CCC[Mg]Cl)CCC Chemical compound C(CC)C(=CCC[Mg]Cl)CCC NNSDCLUPQZHWMT-UHFFFAOYSA-M 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
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- 241000282412 Homo Species 0.000 description 1
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- 241000124008 Mammalia Species 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
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- 235000011054 acetic acid Nutrition 0.000 description 1
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- 125000002015 acyclic group Chemical group 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
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- 238000007865 diluting Methods 0.000 description 1
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
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- 235000013922 glutamic acid Nutrition 0.000 description 1
- 230000035929 gnawing Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- BICAGYDGRXJYGD-UHFFFAOYSA-N hydrobromide;hydrochloride Chemical compound Cl.Br BICAGYDGRXJYGD-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- ZKUUVVYMPUDTGJ-UHFFFAOYSA-N methyl 5-hydroxy-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(O)=C(OC)C=C1[N+]([O-])=O ZKUUVVYMPUDTGJ-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C21/00—Acyclic unsaturated compounds containing halogen atoms
Definitions
- the present invention relates to a new process for producing 2-(3-(4-propylheptyl)morpholino)ethan-1-ol with the INN name delmopinol.
- the invention also discloses three intermediates 1-chloro-4-propylhept-3-ene, 1-iodo-4-propylhept-3-ene and 2-(3-(4-propylhept-3-en-1-yl)morpholino)ethan-1-ol for said process.
- Delmopinol is used in the treatment of gingivitis, prevention of plaque formation and for oral hygiene in general in humans. It is used as an active component in mouth wash liquids and toothpaste. It is also used in the maintenance of oral health in animals as described in WO 2007/099302 .
- Several methods for synthesis of delmopinol have been disclosed (e.g. WO 90/14342 and WO 2007/091009 ) and an industrially applicable method disclosed in WO 2007/057681 .
- WO 2007/057681 describes the preparation of 1-halo-4-propylheptane by halogenation of 4-propylheptan-1-ol.
- preparation of 1-bromo-4-propylheptane by treatment with aqueous hydrogen bromide The preparation of 4-propylheptan-1-ol is obtained according to Justus Liebigs Ann. Chem. 1966, 693, 90-98 describing the synthesis of 4-propylheptan-1-ol in four steps in 58% overall yield from -butyrolactone which is a controlled substance with use restrictions.
- WO 2007/057681 describes the preparation of 1-halo-4-propylheptane by halogenation of 4-propylheptan-1-ol.
- 1-bromo-4-propylheptane by treatment with aqueous hydrogen bromide.
- the preparation of 4-propylheptan-1-ol is obtained according to Justus Liebigs Ann. Chem. 1966, 693
- the present invention relates to a new process for producing delmopinol, 2-(3-(4-propylheptyl)morpholino)ethan-1-ol.
- the invention provides a process for the manufacturing of delmopinol, which process comprises the use of 1-halo-4-propylhept-3-ene.
- the invention further provides a process for manufacturing of delmopinol, which process comprises the use of 2-(3-(4-propylhept-3-en-1-yl)morpholino)ethan-1-ol.
- One embodiment of the process is briefly illustrated below.
- the invention relates to delmopinol directly obtained by the process described above.
- the invention further discloses the intermediates 1-chloro-4-propylhept-3-ene, 1-iodo-4-propylhept-3-ene and 2-(3-(4-propylhept-3-en-1-yl)morpholino)ethan-1-ol and their use in the manufacturing of delmopinol.
- delmopinol is intended to include any form of the compound, such as the free base and pharmaceutically acceptable salts. Particular mention is made of the hydrochloride salt.
- the free base and pharmaceutically acceptable salts include anhydrous forms and solvated forms such as hydrates.
- the anhydrous forms and the solvates include amorphous and crystalline forms.
- delmopinol encompasses the racemate and the pure enantiomers and mixtures of the enantiomers in any ratio.
- halo indicates bromo or chloro or iodo. In a preferred embodiment, "halo" indicates chloro.
- the compound "1-halo-4-propylhept-3-ene” indicates 1-bromo-4-propylhept-3-ene or 1-chloro-4-propylhept-3-ene or 1-iodo-4-propylhept-3-ene.
- C 1-4 alkyl indicates an alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl and 2-methylpropyl. In a preferred embodiment, "C 1-4 alkyl” indicates methyl.
- HX indicates a halogenhydric acid such as hydrogen chloride, hydrogen bromide or hydrogen iodide.
- purity indicates the percentage by area of the product determined by a chromatographic method, such as gas liquid chromatography, GC.
- say indicates the percentage by weight of the product in a given mixture determined by e.g. potentiometric titration.
- Pharmaceutically acceptable salts in the present context is intended to indicate non-toxic, i.e. physiologically acceptable salts.
- the term pharmaceutically acceptable salts includes salts formed with inorganic and/or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitrous acid, sulphuric acid, benzoic acid, citric acid, gluconic acid, lactic acid, maleic acid, succinic acid, tartaric acid, acetic acid, propionic acid, oxalic acid, maleic acid, fumaric acid, glutamic acid, pyroglutamic acid, salicylic acid, saccharin and sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid and benzenesulfonic acid.
- acids listed above are di- or tri-acids, i.e. acids containing two or three acidic hydrogens, such as phosphoric acid, sulphuric acid, fumaric acid and maleic acid.
- a pharmaceutically acceptable salt is formed with hydrochloric acid
- the inventors have found an improved process for producing delmopinol, 2-(3-(4-propylheptyl)mor-pholino)ethan-1-ol starting from 1-halo-4-propylhept-3-ene.
- the inventors found that the compound 1-halo-4-propylhept-3-ene, wherein halo is bromo, chloro or iodo, preferably 1-chloro-4-propylhept-3-ene, constitutes a good starting material for the manufacturing of delmopinol.
- the Grignard reagent of 1-halo-4-propylhept-3-ene is reacted with oxazolidin[2,3-c]morpholine to obtain the intermediate 2-(3-(4-propylhept-3-en-1-yl)morpholino)ethan-1-ol, which is then converted to delmopinol by catalytic hydrogenation.
- delmopinol obtained as described above may be reacted with an appropriate acid to obtain a pharmaceutically acceptable salt of delmopinol.
- the manufacturing of oxazolidin[2,3-c]morpholine has been described e.g. in WO 2007/057681 .
- Suitable solvents for the Grignard reagent preparation and the coupling with oxazolidin[2,3-c]morpholine include cyclic and acyclic ethers and their mixtures with alkyl or aryl hydrocarbons; preferably the reaction is conducted in an ethereal solvent, more preferably the reaction is conducted in THF (tetrahydrofuran).
- the coupling of (4-propylhept-3-en-1-yl)magnesium halide with oxazolidin[2,3-c]morpholine is conducted at a temperature from -20 to 60°C, preferably from 10 to 30°C.
- the organomagnesium reagent is used in a ratio from 0.9 to 1.5 equivalents relative to oxazolidin[2,3-c]morpholine, preferably from 1.0 to 1.3 equivalents.
- 2-(3-(4-Propylhept-3-en-1-yl)morpholino)ethan-1-ol is isolated from the Grignard reaction mixture using the methods known to the person skilled in the art and reduced by catalytic hydrogenation to obtain delmopinol.
- the hydrogenation can be achieved in a solvent, such as an alcohol, an ether, an ester, a hydrocarbons, an organic acid or a mixture thereof, preferably in an alcohol and even more preferably in methanol.
- the catalyst is selected among transition metal elements, preferably the catalyst is palladium based.
- the catalytic hydrogenation is run at a temperature comprised in the range from 20 to 60°C and a H 2 pressure from 1 to 6 bar.
- Delmopinol obtained in the hydrogenation can be purified by any of the methods known to the person skilled in the art e.g. by distillation or acid-base treatment.
- delmopinol obtained by the above process can be prepared by any of the methods known to the person skilled in the art.
- delmopinol may be reacted with an appropriate acid selected from the acids disclosed above.
- the present invention discloses delmopinol directly obtained by the process described above. In a further embodiment, the present invention discloses highly pure delmopinol directly obtained by the process described above.
- H + is a halogenhydric acid (HX) or a non-halogenhydric acid.
- H + is a halogenhydric ac-id such as hydrogen chloride, hydrogen bromide or hydrogen iodide, preferably hydrogen chloride.
- a cyclopropanecarbonyl derivative (I) is reacted with a propylmagnesium halide (II) to give 4-cyclopropylheptan-4-ol (III).
- the alcohol (III) is then treated with a suitable halogenhydric acid to afford the desired 1-halo-4-propylhept-3-ene (IV).
- Suitable cyclopropanecarbonyl derivatives include C 1-4 alkyl-esters of cyclopropanecarboxylic acid, preferably methyl cyclopropanecarboxylate; and cyclopropylcarbonyl halides, preferably cyclopropanecarbonyl chloride.
- the organomagnesium reagent (II) of 1-halopropane where the halogen is chloro, bromo or iodo, preferably 1-bromopropane or 1-chloropropane, is used in a ratio from 2 to 3 equivalents vs. the carbonyl derivative (I), preferably from 2 to 2.3 equivalents.
- Suitable solvents for the Grignard coupling include a cyclic and an acyclic ether and their mixtures with an alkyl or an aryl hydrocarbon; preferably the reaction is conducted in an ethereal solvent, more preferably the reaction is performed in THF.
- the transformation of (III) into (IV) is achieved using from 1 to 2 equivalents of halogenhydric acid HX relative to the cyclopropylcarbonyl derivative (I), preferably 1.5 eq.
- the transfor-mation of (III) into (IV) can be accomplished in the presence of an organic solvent such as an ether, a hydrocarbon or an ester or a mixture thereof.
- an organic solvent such as an ether, a hydrocarbon or an ester or a mixture thereof.
- the reaction is run in an ethereal solvent, more preferably the reaction is run in THF.
- the reaction is conducted at a temperature from 0°C to reflux until the conversion to 1-halo-propylhept-3-ene is complete.
- magnesium 4-cyclopropylheptan-4-olate halide originated from the reaction of the cyclopropylcarbonyl derivative (I) where R is OAlk, and propylmagnesium hal-ide (II), is treated with a non halogenhydric acid such as sulfuric acid, perchloric acid or fluorosulfuric acid, affording directly the desired 1-halo-propylhept-3-ene having the same halogen as the starting propylmagnesium halide (II).
- Suitable cyclopropanecarbonyl derivatives include C 1-4 alkyl-esters of cyclopropanecarboxylic acid, preferably methyl cyclopropanecarboxylate.
- the inventors have found that the transformation can be accomplished using the non halogenhydric acid in only smal excess thus limiting unwanted side reactions and the wastes and obtaining compound (IV) in a high purity suitable for further processing to delmopinol.
- the transformation using a non halogenhydric acid is obtained using from 1 to 2.5 mol of acid per mol of 1-halopropane, preferably from 1 to 2.
- the present invention also discloses a pharmaceutical composition
- a pharmaceutical composition comprising delmopinol obtained by the process of the invention.
- the pharmaceutical composition may further comprise at least one pharmaceutically acceptable excipient, carrier and/or diluent.
- Methods for the preparation of pharmaceutical compositions such as liquid pharmaceutical compositions are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins (2005 ).
- the pharmaceutical composition can be for human use or for veterinary use.
- Pharmaceutical compositions comprising delmopinol obtained according to the present invention are intended for local administration in the oral cavity.
- the pharmaceutical composition for human use is preferably a liquid composition comprising delmopinol in a therapeutically effective amount, preferably as delmopinol HCl.
- the pharmaceutical composition can for example be a mouth wash product or a toothpaste. It is envisaged that a pharmaceutical composition for human use comprising delmopinol obtained by a process of the invention may be used for treatment of oral diseases such as gingivitis or for prevention of plaque formation. In one embodiment, the composition may be used for general oral hygiene.
- the pharmaceutical composition for human use comprising delmopinol obtained by the process of the invention is a liquid composition comprising delmopinol HCI in a concentration of 1-5%, such as about 1%, 2%, 3%, 4% or 5%, preferably about 2%.
- Said pharmaceutical composition is preferably a mouth wash product or a toothpaste.
- compositions for veterinary use comprising delmopinol have been described in WO 2007/099302 .
- a pharmaceutical composition for veterinary use is an animal chew wherein the term chew is given its normal meaning in the art and refers to any toy, accessory or foodstuff that is intended for chewing or gnawing by an animal ( WO 2007/099302 .
- the pharmaceutical composition for veterinary use is for use in the treatment of a pet such as a cat or a dog, most preferably a dog.
- Further variations of compo-sitions for veterinary use comprising delmopinol have been disclosed in WO 2007/099302 which is incorporated herein by reference.
- the invention discloses a mouth wash product or a toothpaste comprising delmopinol obtained by the process of the invention.
- the invention discloses an animal chew comprising delmopinol obtained by the process of the invention.
- said animal chew is for use in the treatment of a dog.
- the invention discloses delmopinol obtained by the process of the invention for use in the treatment oral diseases such as gingivitis, or for prevention of plaque formation.
- terapéuticaally effective amount means an amount sufficient to alleviate, arrest, partly arrest or delay progress of the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to accomplish this is defined as “therapeutically effective amount”. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.
- treatment or “treating” is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting or delaying progress of the clinical manifestation of the disease.
- the patient to be treated is preferably a mammal, in particular a human being.
- E1-E37 and E56-E60 of the invention are disclosed.
- the first embodiment is denoted E1
- the second embodiment is denoted E2 and so forth.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT102016000130538A IT201600130538A1 (it) | 2016-12-23 | 2016-12-23 | Processo per la produzione del delmopinolo |
PCT/EP2017/083768 WO2018115096A1 (en) | 2016-12-23 | 2017-12-20 | Method for the manufacturing of delmopinol |
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EP3558951B1 true EP3558951B1 (en) | 2021-04-14 |
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US (1) | US10894778B2 (da) |
EP (1) | EP3558951B1 (da) |
DK (1) | DK3558951T3 (da) |
ES (1) | ES2871824T3 (da) |
IT (1) | IT201600130538A1 (da) |
WO (1) | WO2018115096A1 (da) |
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IT201600130729A1 (it) | 2016-12-23 | 2018-06-23 | Lundbeck Pharmaceuticals Italy S P A | Processo per la produzione degli intermedi del delmopinolo |
US11780818B2 (en) | 2020-01-31 | 2023-10-10 | You First Services, Inc. | Methods of making delmopinol and salts thereof |
Citations (2)
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WO2018115111A1 (en) * | 2016-12-23 | 2018-06-28 | Lundbeck Pharmaceuticals Italy S.P.A. | Method for the manufacturing of 2-(3-(alkyl and alkenyl)morpholino)-ethan-1-ols |
WO2018115116A1 (en) * | 2016-12-23 | 2018-06-28 | Lundbeck Pharmaceuticals Italy S.P.A. | Method for the manufacturing of delmopinol intermediates |
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SE439011B (sv) | 1980-03-21 | 1985-05-28 | Ferrosan Ab | Morfolinoforeningar, kompositioner innehallande dessa och anvendning derav |
WO1990014342A1 (en) * | 1989-05-24 | 1990-11-29 | Pharmacia Ab | Substituted isoxazolidines and isoxazolines |
GB0509437D0 (en) * | 2005-05-09 | 2005-06-15 | Sinclair Pharmaceuticals Ltd | Method |
GB0515138D0 (en) * | 2005-07-22 | 2005-08-31 | Sinclair Pharmaceuticals | Acne treatment |
GB0523435D0 (en) * | 2005-11-17 | 2005-12-28 | Sinclair Pharmaceuticals Ltd | Process |
GB0602424D0 (en) * | 2006-02-07 | 2006-03-22 | Sinclair Pharmaceuticals Ltd | Compounds |
GB0604018D0 (en) | 2006-02-28 | 2006-04-05 | Sinclair Pharmaceuticals Ltd | Method |
GB0708960D0 (en) * | 2007-05-09 | 2007-06-20 | Sinclair Pharmaceuticals Ltd | Method |
GB201105162D0 (en) * | 2011-03-28 | 2011-05-11 | Lane Jonathan | Improved deodorant formulations |
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- 2017-12-20 EP EP17821624.8A patent/EP3558951B1/en active Active
- 2017-12-20 ES ES17821624T patent/ES2871824T3/es active Active
- 2017-12-20 US US16/472,367 patent/US10894778B2/en active Active
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WO2018115111A1 (en) * | 2016-12-23 | 2018-06-28 | Lundbeck Pharmaceuticals Italy S.P.A. | Method for the manufacturing of 2-(3-(alkyl and alkenyl)morpholino)-ethan-1-ols |
WO2018115116A1 (en) * | 2016-12-23 | 2018-06-28 | Lundbeck Pharmaceuticals Italy S.P.A. | Method for the manufacturing of delmopinol intermediates |
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EP3558951A1 (en) | 2019-10-30 |
DK3558951T3 (da) | 2021-05-25 |
US20190375722A1 (en) | 2019-12-12 |
WO2018115096A1 (en) | 2018-06-28 |
IT201600130538A1 (it) | 2018-06-23 |
US10894778B2 (en) | 2021-01-19 |
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